Everolimus (RAD-001) is the 40-O-(2-hydroxyethyl)-rapamycin of formula (I),

It is a derivative of sirolimus of formula (III),
and works similarly to sirolimus as an inhibitor of mammalian target of rapamycin (mTOR). Everolimus is currently used as an immunosuppressant to prevent rejection of organ transplants and treatment of renal cell cancer and other tumours. It is marketed by Novartis under the tradenames Zortress™ (USA) and Certican™ (Europe and other countries) in transplantation medicine, and Afinitor™ in oncology.
Trisubstituted silyloxyethyltrifluoromethane sulfonates (triflates) of the general formula (IV),
wherein R1, R2, R3 are independently a straight or branched alkyl group, for example C1-C10 alkyl, and/or an aryl group, for example a phenyl group, are important intermediates useful in the synthesis of everolimus.
Everolimus and its process for manufacture using the intermediate 2-(t-butyldimethyl silyl) oxyethyl triflate of formula (IVA),
was first described in U.S. Pat. No. 5,665,772. The overall reaction is depicted in Scheme I.

For the synthesis, firstly sirolimus of formula (III) and 2-(t-butyldimethylsilyl)oxyethyl triflate of formula (IVA) are reacted in the presence of 2,6-Lutidine in toluene at around 60° C. to obtain the corresponding 40-O-[2-(t-butyldimethylsilyl)oxy]ethyl rapamycin of formula (IIa), which is then deprotected in aqueous hydrochloric acid and converted into crude everolimus [40-O-(2-Hydroxy)ethyl rapamycin] of formula (I).
However, this process results in the formation of impure everolimus, which requires purification by column chromatography. The process results in very poor overall yield and purity and thereby the process is not suitable for the commercial scale production of everolimus.
Moenius et al. (I. Labelled Cpd. Radiopharm. 43, 113-120 (2000) have disclosed a process to prepare C-14 labelled everolimus using the diphenyltert-butylsilyloxy-protective group of formula (IV B),
as the alkylation agent. The overall yield reported was 25%.
International patent application, publication number WO 2012/103960 discloses the preparation of everolimus using the alkylating agent 2-((2,3-dimethylbut-2-yl)dimethylsilyloxy)ethyl triflate of formula (IVC),
wherein the overall yield reported is 52.54%. The process involves a derivatization method based on the reaction of the triflate (IV) with a derivatization agent, which preferably is a secondary aromatic amine, typically N-methylaniline.
International patent application, publication number WO 2012/103959 also discloses the preparation of everolimus using the alkylating agent of formula (IVC). The process is based on a reaction of rapamycin with the compound of formula (IVC) in the presence of a base (such as an aliphatic tertiary amine) to form 40-O-2-(t-hexyldimethylsiloxy)ethylrapamycin, which is subsequently deprotected under acidic conditions to obtain everolimus.
European Patent Number 1518517B discloses a process for the preparation of everolimus which employs the triflate compound of formula (IVA), 2-(t-butyldimethyl silyl) oxyethyl triflate. The disclosed process for preparing the compound of formula (IVA) involves a flash chromatography purification step.
The compounds of formula (IV) are key intermediates in the synthesis of everolimus. However, they are highly reactive and also very unstable, and their use often results in decomposition during reaction with sirolimus. This is reflected by the fact that the yields of the reaction with sirolimus are very low and the compounds of formula (IV) are charged in high molar extent. Thus it is desirable to develop a process to stabilize compounds of formula (IV) without loss of reactivity.